Architectural space layout has proven to be influential on building energy performance. However, the relationship between different space layouts and their consequent energy demands has not yet been systematically studied. This study thoroughly investigates such a relationship. In order to do so, a computational method was developed, which includes a method to generate space layouts featuring energy-related variables and an assessment method for energy demand. Additionally, a design of experiments was performed, and its results were used to analyse the relationship between space layouts and energy demands. In order to identify their relationship, four types of design indicators of space layout were proposed, both for the overall layout and for each function. Finally, several optimisations were performed to minimise heating, cooling and lighting demands. The optimisation results showed that the maximum reduction between different layouts was up to 54% for lighting demand, 51% for heating demand and 38% for cooling demand. The relationship analysis shows that when comparing the four types of design indicators, the façade area-to-floor area ratio showed a stronger correlation with energy demands than the façade area ratio, floor area ratio and height-to-depth ratio. Overall, this study shows that designing a space layout helps to reduce energy demands for heating, cooling and lighting, and also provides a reference for other researchers and designers to optimise space layout with improved energy performance.